Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. At present, an estimated 2.3 million people are diagnosed with AF in the United States, and this number is expected to rise to 3.3 million by 2020. This rapid increase in AF prevalence is not entirely explained by the aging of the population. Women with AF have higher mortality and stroke rates compared to their male counterparts;and AF is the most common cause of stroke among elderly women. AF also leads to a greater impairment of quality of life among women. Therefore, research directed at the prevention of AF in women is needed. This R21 application resubmitted in response to PA-06-181, NIH Exploratory-Developmental Research Grant program, proposes to utilize an ongoing, well-characterized prospective cohort of 39,876 female health professionals who have been followed for a variety of interrelated medical conditions over 14 years to effectively address important hypotheses with respect to prediction and prevention of AF among women. Extensive updated data on epidemiologic exposures have been collected in the entire cohort along with an extensive list of measured biomarkers in the 28,345 who donated blood samples at baseline. The relationship between selected markers and modulators of inflammation and oxidative stress, components of the metabolic syndrome, and specific nutrients and risk of subsequent AF will be examined. Biomarkers to be examined include hsCRP, Fibrinogen, ICAM-1, Lp (a), HgbA1C, and lipid levels. Traditional epidemiologic exposures include measures of adiposity, diabetes, and exercise, as well as nutritional exposures including dietary fat and flavonoid intake. The relationship between randomized vitamin E treatment and non-randomized statin therapy and AF will also be assessed. For many of the exposures, specific relations for patterns and subtypes of AF will also be explored. The estimated 1296 confirmed AF cases, of which an estimated 1001 will have stored blood samples, will comprise the largest number of AF cases among women and will serve as a unique resource for these and other future epidemiologic, biomarker, and genetic analyses. The results from these studies may identify potentially modifiable metabolic and dietary factors that could potentially protect against atrial fibrillation, and may also provide insights into underlying mechanisms of atrial fibrillation among women. This knowledge may ultimately lead to a reduction in AF incidence and prevalence, a disease leading to strokes, heart failure and death. PUBLIC HEALTH RELEVANCE: The goal of this research is to identify potentially modifiable factors that predispose women to develop the most common sustained heart rhythm disturbance, atrial fibrillation. Among women, atrial fibrillation accounts for approximately 15% of strokes and can significantly impair physical functioning and quality of life. Once established, atrial fibrillation is difficult to treat;and therefore, research directed at prevention of atrial fibrillation is essential for women. The results from these studies may identify lifestyle changes and possible medications that could potentially prevent atrial fibrillation among women.